Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders
Ali Abbara, … , Aylin Hanyaloglu, Waljit S. Dhillo
Ali Abbara, … , Aylin Hanyaloglu, Waljit S. Dhillo
Published November 16, 2020
Citation Information: J Clin Invest. 2020;130(12):6739-6753. https://doi.org/10.1172/JCI139681.
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Clinical Research and Public Health Endocrinology Reproductive biology

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders

Abstract

BACKGROUND Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODS We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTS In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSION Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATION International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDING National Institute for Health Research and NIH.

Authors

Ali Abbara, Pei Chia Eng, Maria Phylactou, Sophie A. Clarke, Rachel Richardson, Charlene M. Sykes, Chayarndorn Phumsatitpong, Edouard Mills, Manish Modi, Chioma Izzi-Engbeaya, Debbie Papadopoulou, Kate Purugganan, Channa N. Jayasena, Lisa Webber, Rehan Salim, Bryn Owen, Paul Bech, Alexander N. Comninos, Craig A. McArdle, Margaritis Voliotis, Krasimira Tsaneva-Atanasova, Suzanne Moenter, Aylin Hanyaloglu, Waljit S. Dhillo

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Figure 1

Study protocol.

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Study protocol. Study participants were admitted to the Clinical Researc...
Study participants were admitted to the Clinical Research Facility at 8 am on the morning of each study visit. An i.v. cannula was inserted into one antecubital fossa, and blood was sampled at T –30 minutes, T –15 minutes, and T = 0 hours before administration of each intervention to determine the basal hormonal values. An s.c. bolus of kisspeptin-54 (KP54) or 0.9% saline (A), or of MVT-602 (B), was administered at T = 0 hours. (A) Study protocol diagram for the KP54 and 0.9% saline visits. After an s.c. bolus of KP54 (9.6 nmol/kg) or 0.9% saline at T = 0 hours, serum hormone levels (LH, FSH, estradiol, and progesterone) were measured every 5–15 minutes for the first 30 minutes, and then every 30 minutes until 10 hours, and additionally at 24 hours. (B) Study protocol diagram for MVT-602 visits. After an s.c. bolus of MVT-602 (0.03 nmol/kg) was administered at T = 0 hours, serum hormone levels (LH, FSH, estradiol, and progesterone) were measured every 5–15 minutes for the first 30 minutes, then every 30 minutes until 14 hours, and then every 60 minutes until 24 hours and additionally at 28, 32, and 48 hours. A further blood test at 72 hours was carried out in studies using estradiol pretreatment.